Methods For Treating Inflammatory Conditions

ABSTRACT

The present invention relates to compounds and pharmaceutically acceptable salts thereof and formulations comprising tenilsetam or pharmaceutically acceptable salts thereof that are useful in modulating inflammation. In particular, the compounds or pharmaceutically acceptable salts thereof are useful for treating or preventing a disease or disorder involving inflammation, including, but not limited to, delayed type hypersensitivity and contact hypersensitivity.

FIELD OF THE INVENTION

The present invention is directed to methods of preventing or treatingan inflammatory disease or condition in a mammal comprisingadministering a tenilsetam-related compound.

BACKGROUND OF THE INVENTION

Delayed-type hypersensitivity (DTH) reactions are antigen-specificcell-mediated immune responses that can mediate harmful (e.g., allergicdermatitis and autoimmunity) aspects of immune function. The immunereaction is characterized by swelling at the site of challenge and by aninfiltration of monocytes/macrophages and lymphocytes into the epidermisand dermis. Type IV or DTH, is most seriously manifested when antigens(for example those of tubercle bacilli) are trapped in a macrophage andcannot be cleared. T cells are then stimulated to elaborate lymphokineswhich mediate a range of inflammatory responses. Other aspects of DTHreactions are seen in graft rejection and allergic contact dermatitis.DTH is used as a general category to describe all those hypersensitivityreactions which take more than 12 hours to develop, and which involvecell-mediated immune reactions rather than humoral immune reactions.Whereas allergic reactions occur within seconds and minutes and immunecomplex reactions occur within several hours to one day, DTH reactionspeak at 2 to 3 days.

Unlike other forms of hypersensitivity, type IV hypersensitivity cannotbe transferred from one animal to another by serum, but can betransferred by T cells (TH1 cells in mice). In humans, transfer from asensitized to a non-sensitized individual can be also achieved only by Tlymphocytes and, interestingly, by a low molecular weight materialextracted from them (transfer factor). DTH is associated with T cellprotective immunity but does not necessarily run parallel with it—thereis not always a complete correlation between delayed hypersensitivityand protective immunity. The T cells necessary for producing the delayedresponse are cells which have become specifically sensitized to theparticular antigen by a previous encounter, and they act by recruitingother cell types to the site of the reaction.

Three types of delayed hypersensitivity reaction are recognized: Contacthypersensitivity and tuberculin-type hypersensitivity both occur within72 hours of antigen challenge, whereas granulomatous reactions developover a period of weeks. The granulomas are formed by the aggregation andproliferation of macrophages, and may persist for weeks. This reactionis, in terms of its clinical consequences, by far the most serious typeof DTH response. The position is complicated because these differenttypes of reaction may overlap, or occur sequentially following a singleantigenic challenge.

The DTH reactions are likely important for host defense againstintracellular parasites such as tuberculosis and certain viruses and areprevalent in certain disease such as sarcoidosis, Wegener'sgranulomatosis, and polymyositis. In some diseases, such as chronicgranulomatous disease of childhood, granuloma formation can lead toobstruction of vital structures such as the esophagus or ureters.

Contact hypersensitivity, or contact dermatitis, is a T cell-mediatedcutaneous immune/inflammatory reaction to haptens. Typicalmanifestations of contact dermatitis include, but are not limited to,rashes, dermatoses, and skin eruptions, which can be treated topicallyto improve or favorably alter the disease condition. Such rashes,dermatoses or skin eruptions include acute, inflammatory reactions ofthe skin caused by an allergic or irritant reaction (such as that causedby, for example, poison ivy, poison oak or poison sumac, or other formsof allergic or irritant contact dermatitis), other forms of eczema,lichen simplex chronicus, rashes, dermatoses or skin eruptions of achronic nature (such as, for example, seborrheic dermatitis, psoriasis,atopic dermatitis) or caused by infection, irritation or aggravation ofanother condition such as occurs with acne, and other rashes, dermatosesor skin eruptions.

Contact dermatitis may be produced by primary irritants or allergicsensitizes. Irritant contact dermatitis is a nonallergic reaction of theskin caused by exposure to irritating substances. Most primary irritantsare chemical substances, although physical and biologic (infectious)agents may produce the same reaction. Irritants account for 80% ofoccupational contact dermatitis and also cause the most frequent type ofnon-industrial contact reaction. Allergic contact dermatitis is amanifestation of delayed hypersensitivity and results from the exposureof sensitized individuals to contact allergens. Poison ivy and poisonoak induce sensitization in more than 70% of the population, therebycausing allergic contact dermatitis (Arndt, Kenneth A., Manual ofDermatologic Therapeutics, 5th edition, 1995, Little, Brown and Co.,page 49).

Irritants may cause an inelastic and stiff-feeling skin, discomfort dueto dryness, pruritus secondary to inflammation, and pain due tofissures, blisters, and ulcers. Mild irritants produce erythema,microvesiculation, and oozing that may be indistinguishable fromallergic contact dermatitis. Chronic exposure to mild irritants orallergens results in dry, thickened, and fissured skin. Strong irritantscause blistering, erosion, and ulcers of the skin. Allergic contactdermatitis, in its mild form, is similar in appearance to the irritanteruption. A more typical allergic contact reaction may consist ofgrouped or linear tense vesicles and blisters. If involvement is severethere may be marked edema, particularly of the face and in theperiorbital and genital areas.

Generally, eczematous dermatitides include a group of diseases whichpresent with a common morphology: erythematous and papulovesicular whenacute; erythematous and scaling (with or without fissures andlichenification) when chronic. Included under this rubric are atopicdermatitis, contact dermatitis, nummular dermatitis, seborrheicdermatitis and stasis dermatitis.

Atopic dermatitis is a common infantile eczema which affectsapproximately 10-20% of children in the United States. The disease has astrong association with allergic rhinitis and asthma and occurs inapproximately one-third of children with a personal or family history ofthese disorders. Although IgE antibodies may be elevated in up to 80% ofindividuals with atopic dermatitis, the skin manifestations do not seemto be a purely IgE-mediated process. The etiology of atopic dermatitisis unknown. Current hypotheses have concentrated on the possibility thatan aberrant T cell response, perhaps to staphylococcal superantigen,results in the activation of T_(H)2 cells.

Clinically, atopic dermatitis has been called the “itch that rashes.”Pruritus is a hallmark of the disease. Infants less than 18 months ofage typically present with an acute to subacute dermatitis which mayinvolve the scalp, the face (particularly the cheeks), the posteriorneck, the trunk and the extensor aspects of the extremities. Afterapproximately two years of age, most individuals will present with amore chronic, lichenified and scaling form of the disease distributedabout the face, neck, trunk and especially the flexural aspects of theextremities (antecubital and popliteal fossae). The reason for thechange in distribution of the dermatitis on the extremities is notclear. Individuals with atopic dermatitis are prone to develop secondaryinfection with staphylococcal organisms, as well as with viruses andfungi. When the disease is flaring, these secondary infections must beexcluded.

Contact Dermatitis, also described above, can be broken down into twomain areas: irritant contact dermatitis and allergic contact dermatitis.

Irritant contact dermatitis is the direct result of injury to the skincaused by chemical exposure. Irritation can be further subdivided intoacute corrosion (caused by a single exposure to strong acids andalkalis), acute irritation (caused by a single exposure to chemicalssuch as strong solvents and non-corrosive acids and bases), cumulativeirritation (the most typical and caused by repeated exposuresparticularly to surfactants and emulsifiers) and phototoxicity (causedby exposure to irritating chemicals which require light for theiractivation). The clinical presentation of irritation can therefore varyfrom the acute onset of a third degree chemical burn (corrosionfollowing phenol exposure) to the chronic scaling and xerotic dermatitisof “dishpan hands.” Because irritant contact dermatitis is a function ofthe chemical, it will occur in all individuals exposed to this chemicalgiven sufficient exposure times and concentrations. Nonetheless, it isclear that the skin of some individuals is much more irritable thanothers. The determinants of hyperirritable skin are numerous and includeage, genetics, ambient environment, underlying skin disease(s), andconcomitant chemical exposure.

Allergic contact dermatitis (ACD) develops following exposure tochemicals to which the individual has previously become sensitized. Itis a type IV or delayed-type hypersensitivity reaction of the skin.There are over 3,000 environmental allergens which have been reported tocause this condition. The prevalence of ACD varies with the allergen.Typically, the patient will develop an erythematous, scaling,papulovesicular dermatitis at the sites of contact with the allergen.Longstanding, low grade allergens can create a more subacute to chronic,scaling lichenified dermatitis.

Nummular dermatitis is characterized by its “coin-shaped” lesions. Aswith other dermatitides, the acute form is papulovesicular whereas thechronic form is scaly and lichenified. Mild to severe pruritusaccompanies the disease which most frequently affects men, typically inthe sixth decade or beyond. The prevalence of the disease is unknown,but it would appear to be lower than that for most of the other eczemas.

Seborrheic dermatitis is one of the most common cutaneous diseases andaffects from 3 to 5% of the population. One proposed etiology isovergrowth of Pityrosporum, a yeast that normally inhabits sebaceousskin (e.g., scalp, eyebrows, central face). The disease has two peaks,one in infancy and the other post-pubertal. Infantile seborrheicdermatitis typically occurs within the first months of life and affectsthe scalp (“cradle cap”) and intertriginous areas with scales and crust.The skin about the ears and the neck may also be involved. In contrast,seborrheic dermatitis in adults typically involves the scalp, face,neck, mid upper chest and intertriginous zones (axillae, groin,submammary, and in obese patients beneath the pannus). On the face, itparticularly concentrates about the eyebrows, nasolabial folds andretroauricular areas.

Stasis dermatitis is an eczematous process of the skin of the lowerextremities which results from non-specific inflammation presumablyinduced by the leakage of serum secondary to venous hypertension. Thedisease is particularly common over the medial and anterior aspects ofthe shin and malleolar areas. When significant inflammation occurs, itcan be accompanied by a secondary autosensitization dermatitis referredto as an “id.”

SUMMARY OF THE INVENTION

The present invention provides methods of treating an inflammatorydisease or condition in a mammal comprising administering to the mammala therapeutically effective amount of a compound of formula I

wherein: X is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, or phenyl, eachunsubstituted, mono-substituted, di-substituted, or tri-substitutedwith, independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or(C₁-C₄)alkoxy-(C₁-C₄) alkyl; R¹ and R⁴ are, independently, H or C₁-C₄alkyl; R^(2a) and R^(2b) are, independently, H, OH, or C₁-C₄ alkyl, or,together, R^(2a) and R^(2b) are C═O; R^(3a) and R^(3b) are,independently, H, OH, or C₁-C₄ alkyl, or, together, R^(3a) and R^(3b)are C═O; and R^(X) is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; or a pharmaceutically acceptable salt thereof.

In some embodiments, X is 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl,each unsubstituted, mono-substituted, di-substituted, or tri-substitutedwith, independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl. In some embodiments, X is 2-thienyl, 3-thienyl,2-furyl, or 3-furyl, each unsubstituted, mono-substituted, ordi-substituted with, independently, OH, halogen, C₁-C₄ alkyl, or C₁-C₄alkoxy. In some embodiments, X is 2-thienyl or 2-furyl, eachunsubstituted, mono-substituted, or di-substituted with, independently,OH, halogen, or C₁-C₄ alkyl. In some embodiments, X is unsubstituted2-thienyl or 2-thienyl mono-substituted with OH, halogen, or C₁-C₄alkyl. In some embodiments, X is unsubstituted 2-thienyl.

In some embodiments, R¹ and R⁴ are H. In some embodiments, R¹ and R⁴ areC₁-C₄ alkyl.

In some embodiments, R^(2a) and R^(2b) are, independently, H or C₁-C₄alkyl, or, together, R^(2a) and R^(2b) are C═O. In some embodiments,R^(2a) and R^(2b) are, independently, H or OH. In some embodiments,R^(2a) and R^(2b) are both H.

In some embodiments, R^(3a) and R^(3b) are, independently, H or C₁-C₄alkyl, or, together, R^(3a) and R^(3b) are C═O. In some embodiments,R^(3a) and R^(3b) are, independently, H or OH. In some embodiments,R^(3a) and R^(3b) are both H.

In some embodiments, R^(X) is H, C₁-C₄ alkyl, or C₁-C₄ alkoxy. In someembodiments, R^(X) is H or C₁-C₄ alkyl. In some embodiments, R^(X) is H.

In some embodiments, X is 2-thienyl or 2-furyl, each unsubstituted,mono-substituted, or di-substituted with, independently, OH, halogen, orC₁-C₄ alkyl; R^(2a) and R^(2b) are, independently, H or OH; R^(3a) andR^(3b) are, independently, H or OH; and R^(X) is H.

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH, halogen, or C₁-C₄ alkyl; R¹ and R⁴ are,independently, H or C₁-C₄ alkyl; R^(2a) and R^(2b) are, independently, Hor OH; R^(3a) and R^(3b) are, independently, H or OH; and R^(X) is H.

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH, halogen, or C₁-C₄ alkyl; R¹ and R⁴ are H;R^(2a) and R^(2b) are, independently, H or OH; R^(3a) and R^(3b) are,independently, H or OH; and R^(X) is H or halogen.

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH, halogen, or C₁-C₄ alkyl; and R¹, R⁴, R^(2a),R^(2b), R^(3a), R^(3b), and R^(X) are H.

In some embodiments, X is unsubstituted 2-thienyl; R¹ and R⁴ are,independently, H or C₁-C₄ alkyl; R^(2a) and R^(2b) are, independently, Hor OH; R^(3a) and R^(3b) are, independently, H or OH; and R^(X) is H.

In some embodiments, X is unsubstituted 2-thienyl; and R¹, R⁴, R^(2a),R^(2b), R^(3a), R^(3b), and R^(X) are H.

In some embodiments, the compound of formula I, or pharmaceuticallyacceptable salt thereof, is present within a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier.

In some embodiments, the inflammatory disease or condition isdelayed-type hypersensitivity, contact dermatitis, atopic dermatitis, orseptic shock.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph depicting paw swelling in mice after sheep redblood cell challenge following administration of various amounts oftenilsetam.

FIG. 2A is a bar graph of the visual score after skin and earapplication of oxazolone following administration of various amounts oftenilsetam; FIG. 2B is a bar graph of the measured ear thickness afterskin and ear application of oxazolone following administration ofvarious amounts of tenilsetam.

FIG. 3 is a bar graph of TNF levels in lipopolysaccharide challengedmice following administration of various amounts of tenilsetam.

DETAILED DESCRIPTION OF EMBODIMENTS

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise. Thus, forexample, reference to a “cell” is a reference to one or more cells andequivalents thereof known to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals.

As used herein and unless otherwise indicated, the phrase “compounds ofthe invention” means, collectively, compounds of formula I. Thesecompounds are also referred to herein as “tenilsetam-related compounds.”The compounds of the invention are identified herein by their chemicalstructure and/or chemical name. Where a compound is referred to by botha chemical structure and a chemical name, and that chemical structureand chemical name conflict, the chemical structure is determinative ofthe compound's identity.

The compounds of the present invention also include pharmaceuticallyacceptable salts of the compounds disclosed herein. As used herein, thephrase “pharmaceutically acceptable salt” refers to a salt formed by theaddition of a pharmaceutically acceptable acid or base to a compounddisclosed herein. As used herein, the phrase “pharmaceuticallyacceptable” refers to a substance that is acceptable for use inpharmaceutical applications from a toxicological perspective and doesnot adversely interact with the active ingredient. In addition, apharmaceutically acceptable carrier, diluent or excipient is compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. Pharmaceutically acceptable salts, including mono-and bi-salts, include, but are not limited to, those derived fromorganic and inorganic acids such as, but not limited to, acetic, lactic,citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic,ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly knownacceptable acids. Lists of suitable salts are found, for example, inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in theirentireties.

In some embodiments, the acids that may be used to preparepharmaceutically acceptable acid addition salts of such basic compoundsare those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions including, but notlimited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions that are acidic in nature are capable of forming base saltswith various pharmacologically acceptable cations. Examples of suchsalts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium lithium, zinc, potassium, andiron salts.

In some embodiments, the compounds of Formula I may be present in theform of a prodrug. As used herein, “prodrug” refers to a moiety thatreleases a compound of the invention when administered to a patient.Prodrugs can be prepared by modifying functional groups present in thecompounds in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compounds. Examples ofprodrugs include compounds of the invention as described herein thatcontain one or more molecular moieties appended to a hydroxyl, amino,sulfhydryl, or carboxyl group of the compound, and that whenadministered to a patient, cleaves in vivo to form the free hydroxyl,amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,ed. Edward B. Roche, American Pharmaceutical Association and PergamonPress, 1987, both of which are incorporated herein by reference in theirentireties.

As may be appropriate, the compounds in this invention may contain oneor more asymmetric centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. While shown without respect to thestereochemistry in Formula I, the present invention includes suchoptical isomers (enantiomers) and diastereomers (geometric isomers); aswell as the racemic and resolved, enantiomerically pure R and Sstereoisomers; as well as other mixtures of the R and S stereoisomersand pharmaceutically acceptable salts thereof.

Optical isomers can be obtained in pure form by standard proceduresknown to those skilled in the art, and include, but are not limited to,diastereomeric salt formation, kinetic resolution, and asymmetricsynthesis. See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, N.Y., 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972), each of which is incorporated hereinby reference in their entireties. It is also understood that thisinvention may encompass all possible regioisomers, and mixtures thereof,which can be obtained in pure form by standard separation proceduresknown to those skilled in the art, and include, but are not limited to,column chromatography, thin-layer chromatography, and high-performanceliquid chromatography.

Enantiomeric and stereoisomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers andstereoisomers can also be obtained from stereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

As may be appropriate, one skilled in the art will also recognize thatit is possible for tautomers to exist for the compounds of the presentinvention. The present invention includes all such tautomers even thoughnot shown in the formulas herein.

The compounds of the invention also include the solvate and hydrateforms of the compounds. Compounds of the invention can also include allisotopes of atoms occurring in the intermediates or final compounds.Isotopes include those atoms having the same atomic number but differentmass numbers. For example, isotopes of hydrogen include tritium anddeuterium.

The compounds of the invention may also be double-bond isomers (i.e.,geometric isomers).

When administered to a mammal (e.g., to an animal for veterinary use orto a human for clinical use) the compounds of the invention can beadministered in isolated form. As used herein, “isolated” means that thecompounds of the invention are separated from other components of either(a) a natural source, such as a plant or cell, preferably bacterialculture, or (b) a synthetic organic chemical reaction mixture,preferably, via conventional techniques, the compounds of the inventionare purified. As used herein, “purified” means that when isolated, theisolate contains at least 90%, at least 95%, at least 98%, or at least99% of a compound of the invention by weight of the isolate.

The term “improves” is used to convey that the present invention changeseither the appearance, form, characteristics and/or the physicalattributes of the tissue to which it is being provided, applied oradministered. For example, with respect to the skin, the change in formmay be demonstrated by any of the following alone or in combination:enhanced appearance of the skin; increased softness of the skin;increased turgor of the skin; decreased redness; and decreased swelling.

The term “inhibiting” includes the administration of a compound of thepresent invention to prevent the onset of the symptoms, alleviating thesymptoms, or eliminating the disease, condition or disorder.

As used herein and unless otherwise indicated, the term “modulate”refers to a change in the expression and/or activity of a protein, anenzyme, a cell, or a target involved in the disease/disorder pathway. Inan illustrative embodiment, “modulate” refers to the increase ordecrease of the expression and/or activity of a antigen-specific,cell-mediated immune cells, such as T-cells.

Unless otherwise indicated, the term “skin” means that outer integumentor covering of the body, consisting of the dermis and the epidermis andresting upon subcutaneous tissue.

As used herein and unless otherwise indicated, the phrase“therapeutically effective amount” of a composition of the invention ismeasured by the therapeutic effectiveness of a compound of theinvention, wherein at least one adverse effect of a disorder isameliorated or alleviated. In one embodiment, the phrase“therapeutically effective amount” of a composition of the invention ismeasured by the therapeutic effectiveness of a compound of the inventionto alter the expression and/or activity of immune cells, including, butnot limited to T-cells or T-cell mediated reactions.

The term “tissue” refers to any aggregation of similarly specializedcells which are united in the performance of a particular function.

“Treatment” or “treating” refers to an amelioration of a disease ordisorder, or at least one discernible symptom thereof, preferablyassociated with an immune reaction or inflammatory reaction. Treatmentalso refers to an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient. Treatment mayalso include inhibiting the progression of a disease or disorder, eitherphysically, e.g., stabilization of a discernible symptom,physiologically, e.g., stabilization of a physical parameter, or both.

In some embodiments, the compounds of the invention are administered toa mammal in need thereof. That is, the compounds of the invention areadministered to a mammal who has been identified as needinganti-inflammatory treatment.

One embodiment of the present invention encompasses compounds that areeffective in modulating the expression and/or activity of immune cellsboth in vitro and in vivo.

In some embodiments, the present invention provides methods of treatingor preventing an inflammatory disease or condition in a mammalcomprising administering to the mammal a prophylactically ortherapeutically effective amount of a compound of formula I

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, orphenyl, each unsubstituted, mono-substituted, di-substituted, ortri-substituted with, independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or (C₁-C₄) alkoxy-(C₁-C₄) alkyl, or any subgroup thereof.

In some embodiments, X is 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl,each unsubstituted, mono-substituted, di-substituted, or tri-substitutedwith, independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl, or any subgroup thereof.

In some embodiments, X is 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl,each unsubstituted, mono-substituted, or di-substituted with,independently, OH, halogen, C₁-C₄ alkyl, or C₁-C₄ alkoxy, or anysubgroup thereof.

In some embodiments, X is 2-thienyl or 2-furyl, each unsubstituted,mono-substituted, or di-substituted with, independently, OH, halogen, orC₁-C₄ alkyl, or any subgroup thereof.

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH, halogen, or C₁-C₄ alkyl, or any subgroupthereof.

In some embodiments, X is unsubstituted 2-thienyl.

As used herein, the phrase “C₁-C₄” means branched or unbranched alkylgroups having from 1 to 4 carbons, such as, for example, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-buyl.

As used herein, the term “halogen” means F, Cl, I, or Br.

In some embodiments, R¹ and R⁴ are, independently, H or C₁-C₄ alkyl. Insome embodiments, R¹ and R⁴ are H. In some embodiments, R¹ and R⁴ areC₁-C₄ alkyl.

In some embodiments, R^(2a) and R^(2b) are, independently, H, OH, orC₁-C₄ alkyl, or, together, R^(2a) and R^(2b) are C═O, or any subgroupthereof. In some embodiments, R^(2a) and R^(2b) are, independently, H orC₁-C₄ alkyl, or, together, R^(2a) and R^(2b) are C═O, or any subgroupthereof. In some embodiments, R^(2a) and R^(2b) are, independently, H orOH. In some embodiments, R^(2a) and R^(2b) are both H.

In some embodiments, R^(3a) and R^(3b) are, independently, H, OH, orC₁-C₄ alkyl, or, together, R^(3a) and R^(3b) are C═O, or any subgroupthereof. In some embodiments, R^(3a) and R^(3b) are, independently, H orC₁-C₄ alkyl, or, together, R^(3a) and R^(3b) are C═O, or any subgroupthereof. In some embodiments, R^(3a) and R^(3b) are, independently, H orOH. In some embodiments, R^(3a) and R^(3b) are both H.

In some embodiments, R^(X) is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl, or any subgroup thereof. In some embodiments,R^(X) is H, C₁-C₄ alkyl, or C₁-C₄ alkoxy, or any subgroup thereof. Insome embodiments, R^(X) is H or C₁-C₄ alkyl. In some embodiments, R^(X)is H.

In some embodiments, X is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, orphenyl, each unsubstituted, mono-substituted, di-substituted, ortri-substituted with, independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or (C₁-C₄) alkoxy-(C₁-C₄) alkyl, or any subgroup thereof R¹ andR⁴ are, independently, H or C₁-C₄ alkyl; R^(2a) and R^(2b) are,independently, H, OH, or C₁-C₄ alkyl, or, together, R^(2a) and R^(2b)are C═O, or any subgroup thereof R^(3a) and R^(3b) are, independently,H, OH, or C₁-C₄ alkyl, or, together, R^(3a) and R^(3b) are C═O, or anysubgroup thereof and R^(X) is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or(C₁-C₄)alkoxy-(C₁-C₄) alkyl, or any subgroup thereof.

In some embodiments, X is 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl,each unsubstituted, mono-substituted, or di-substituted with,independently, OH, halogen, C₁-C₄ alkyl, or C₁-C₄ alkoxy, or anysubgroup thereof; R¹ and R⁴ are, independently, H or C₁-C₄ alkyl; R^(2a)and R^(2b) are, independently, H, OH, or C₁-C₄ alkyl, or, together,R^(2a) and R^(2b) are C═O, or any subgroup thereof; R^(3a) and R^(3b)are, independently, H, OH, or C₁-C₄ alkyl, or, together, R^(3a) andR^(3b) are C═O, or any subgroup thereof and R^(X) is H, C₁-C₄ alkyl, orC₁-C₄ alkoxy, or any subgroup thereof.

In some embodiments, X is 2-thienyl or 2-furyl, each unsubstituted,mono-substituted, or di-substituted with, independently, OH, halogen, orC₁-C₄ alkyl, or any subgroup thereof; R¹ and R⁴ are H; R^(2a) and R^(2b)are, independently, H or OH; R^(3a) and R^(3b) are, independently, H orOH; and R^(X) is H.

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH, halogen, or C₁-C₄ alkyl, or any subgroupthereof; R¹ and R⁴ are H; R^(2a) and R^(2b) are, independently, H or OH;R^(3a) and R^(3b) are, independently, H or OH; and R^(X) is H.

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH, halogen, or C₁-C₄ alkyl, or any subgroupthereof; R¹ and R⁴ are H; R^(2a) and R^(2b) are H; R^(3a) and R^(3b) areH; and R^(X).

In some embodiments, X is unsubstituted 2-thienyl or 2-thienylmono-substituted with OH or C₁-C₄ alkyl, or any subgroup thereof; andR¹, R⁴, R^(2a), R^(2b), R^(3a), R^(3b), and R^(X) are H.

In some embodiments, X is unsubstituted 2-thienyl; and R¹, R⁴, R^(2a),R^(2b), R^(3a), R^(3b), and R^(X) are H. Such a compound, known astenilsetam, is (+/−)-3-(2-thienyl)-2-piperazinone and its chemicalstructure is depicted below.

In certain embodiments, the compositions or compounds of the inventionare administered to a patient, preferably a human, as a preventativemeasure against such diseases or conditions referred to herein. As usedherein, “prevention” or “preventing” refers to a reduction of the riskof acquiring a given disease or condition. In some embodiments, thecompositions or compounds of the present invention are administered as apreventative measure to a patient, preferably a human, havingdelayed-type hypersentsitivity reactions, dermatitis, contactdermatitis, atopic dermatitis, or other conditions involvinginflammation.

In some embodiments, the compound of formula I, or pharmaceuticallyacceptable salt thereof, is present within a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, as described herein.

In some embodiments, the inflammatory disease or condition is selectedfrom delayed-type hypersensitivity, contact dermatitis, atopicdermatitis, or septic shock.

Diseases or conditions that are not contemplated to be within the scopeof the present invention, and are thus not included within the claimedinvention, include: Alzheimer's disease and Parkinson's disease or othersuch diseases characterized by accumulation of advanced glycation endproducts (AGEs) or any inflammation associated therewith, skin aging,diabetes, early diabetic retinopathy, cerebral hypoxia, cognitivedysfunction, aging, learning deficiency, memory deficiency, bloodplatelet aggregation diseases or conditions, thrombosis, nephritis,allergies such as asthma, pain, convulsive disorders, neurodegeneration,epilepsy, seizure, ictogenesis, epileptogenesis, hypertension, and viralinfections.

Due to the activity of the compounds of the invention, the compounds areadvantageously useful in veterinary and human medicine. As describedabove, the compounds of the invention are useful for the treatment orprevention of disease and disorders associated with immune and/orinflammatory reactions.

The invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acomposition comprising a compound of the invention. The patient is amammal, including, but not limited, to an animal such a cow, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guineapig, or human, or any subgroup thereof. In some embodiments, the mammalis a human.

The present compositions, which comprise one or more compounds of theinvention, can be administered topically.

The topical composition of the present invention can be a cosmetic,cosmeceutical, pharmaceutical or dermatological preparation that isapplied to the skin as a topical cream or liquid solution or dispersion.However, the physical form of the topical composition is not critical.The compositions can also be, for example, formulated as bars, liquids,pastes, mousses, creams, gels, aerosols, lotions, hair shampoos, hairlotions, foam baths, shower baths, alcoholic and aqueous/alcoholicsolutions, emulsions, wax/fat compounds, stick preparations, powders orointments.

The topical compositions of the present invention can be formulated tohave a pH which is similar to the pH of the skin. As such, neutral orslightly acidic pH's are suitable. In particular, the topicalcompositions of the present invention are formulated to have pH ofbetween 4 and 7, or between 4.5 and 5.5.

The topical compositions can be applied by spreading or wiping thecomposition on the skin, or by spraying, dusting, dipping or otherwiseexposing the skin to the topical composition.

In some embodiments, the skin is treated in a non-aerosol manner inorder to avoid promotion of the evaporation of the components. Further,the topical compositions can be stored and/or used in a fashion whichminimizes contact with the air before application to the skin.

The “cosmetic, dermatological or pharmaceutically acceptable carrier”,as used herein, means one or more compatible solid or liquid fillerdiluents or microencapsulating substances which are suitable foradministration to a human or lower animal. Suitable “carriers” should beof sufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the human or lower animal being treated.A safe and effective amount of carrier is from about 50% to about 99.5%,from about 70% to about 99%, or from about 80% to about 90%, of thecomposition.

Variations in formulation of these carriers may result in a wide varietyof products which fall within the scope of the present invention.

The topical compositions of the present invention may be made into awide variety of product types. These include, but are not limited tolotions, creams, beach oils, gels, sticks, sprays, ointments, pastes,mousses and cosmetics. These product types may comprise several types ofcarrier systems including, but not limited to solutions, emulsions, gelsand solids.

The topical composition of the present invention formulated as solutionstypically include a cosmetic, dermatological or pharmaceuticallyacceptable aqueous or organic solvent. The terms “solvent” refers to amaterial which is capable of having dispersed or dissolved therein theactive compounds (namely, the free radical scavenger and the reactivecarbonyl scavenger), and possesses acceptable safety properties (e.g.,with respect to irritation and sensitization characteristics of theskin). Water is a typical aqueous solvent. Examples of suitable organicsolvents include, but are not limited to: propylene glycol, butyleneglycol, polyethylene glycol (200-600), polypropylene glycol (425-2025),glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol,ethanol, isopropanol, butanediol, and mixtures thereof.

If the topical compositions of the present invention are formulated asan aerosol and applied to the skin as a spray-on, a propellant can beadded to a solution composition. Examples of propellants useful hereininclude, but are not limited to, the chlorinated, fluorinated andchloro-fluorinated lower molecular weight hydrocarbons. A more completedisclosure of propellants useful herein can be found in Sagarin,Cosmetics Science and Technology, 2nd Edition, Vol. 2, pp. 443-465(1972).

Topical compositions of the present invention may be formulated as asolution comprising an emollient. An example of a composition formulatedin this way would be a beach oil product. Such compositions can containfrom about 0.1% to about 10% of the active compounds and from about 2%to about 50% of a cosmetic, dermatological orpharmaceutically-acceptable emollient.

As used herein, “emollients” refer to materials used for the preventionor relief of dryness, as well as for the protection of the skin. A widevariety of suitable emollients are known and may be used herein.Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp.32-43 (1972), contains numerous examples of suitable materials.

A lotion can be made from a solution carrier system. Lotions cancomprise from about 0.1% to about 10%, or from about 1% to about 5%, ofthe active compounds; from about 1% to about 20%, or from about 5% toabout 10%, of an emollient; and from about 50% to about 90%, or fromabout 60% to about 80%, water.

Another type of product that may be formulated from a solution carriersystem is a cream. A cream of the present invention can comprise fromabout 0.1% to about 10%, or from about 1% to about 5%, of the activecompounds; from about 5% to about 50%, or from about 10% to about 20%,of an emollient, and from about 45% to about 85%, or from about 50% toabout 75%, water. Yet another type of product that may be formulatedfrom a solution carrier system is an ointment. An ointment may comprisea simple base of animal or vegetable oils or semi-solid hydrocarbons(oleaginous). Ointments may also comprise absorption ointment baseswhich absorb water to form emulsions. Ointment carriers may also bewater soluble. An ointment may also comprise from about 2% to about 10%of an emollient plus from about 0.1% to about 2% of a thickening agent.A more complete disclosure of thickening agents useful herein can befound in Segarin, Cosmetics, Science and Technology, 2nd Edition, Vol.1, pp. 72-73 (1972).

If the carrier is formulated as an emulsion, from about 1% to about 10%,or from about 2% to about 5%, of the carrier system comprises anemulsifier. Emulsifiers may be nonionic, anionic or cationic. Suitableemulsifiers are disclosed in, for example, U.S. Pat. No. 3,755,560,issued Aug. 28, 1973, Dickert et al; U.S. Pat. No. 4,421,769, issuedDec. 20, 1983, Dixon et al.; and McCutcheon's Detergents andEmulsifiers, North American Edition, pages 317-324 (1986). Suitableemulsifiers are anionic or nonionic, although the other types may alsobe used.

Lotions and creams can be formulated as emulsions as well as solutions.Such lotions can comprise from about 0.1% to about 10%, or from about 1%to about 5%, of the active compounds; from about 1% to about 20%, orfrom about 5% to about 10%, of an emollient; from about 25% to about75%, or from about 45% to about 95%, water; and from about 0.1% to about10%, or from about 0.5% to about 5%, of an emulsifier. Such creams cancomprise from about 0.1% to about 10%, or from about 1% to about 5%, ofthe active compounds; from about 1% to about 20%, or from about 5% toabout 10%, of an emollient; from about 20% to about 80%, or from about30% to about 70%, water; and from about 1% to about 10%, or from about2% to about 5%, of an emulsifier.

Single emulsion topical preparations, such as lotions and creams, of theoil-in-water type and water-in-oil type are well-known in the cosmeticart and are useful in the present invention. Multiphase emulsioncompositions, such as the water-in-oil-in-water type, as disclosed inU.S. Pat. No. 4,254,105, are also useful in the present invention. Ingeneral, such single or multiphase emulsions contain water, emollientsand emulsifiers as essential ingredients.

Triple emulsion carrier systems comprising an oil-in-water-in-siliconefluid emulsion composition as disclosed in U.S. Pat. No. 4,960,764, arealso useful in the present invention. This triple emulsion carriersystem can be combined with from about 0.1% to about 10%, or from about1% to about 5%, of the active compounds to yield the topicalcompositions of the present invention.

Another emulsion carrier system useful in the topical compositions ofthe present invention is a microemulsion carrier system. An example ofsuch a system comprises from about 9% to about 15% squalane; from about25% to about 40% silicone oil; from about 8% to about 20% of a fattyalcohol; from about 15% to about 30% of polyoxyethylene sorbitan monofatty acid (commercially available under the trade name Tweens) or othernonionics; and from about 7% to about 20% water. This carrier system canbe combined with from about 1% to about 5% of the active compounds.

If the topical compositions of the present invention are formulated as agel or a cosmetic stick, a suitable amount of a thickening agent, asdisclosed herein, can be added to a cream or lotion formulation.

The topical compositions of the present invention may also be formulatedas makeup products such as foundations.

The topical compositions of the present invention may contain, inaddition to the aforementioned components, a wide variety of additionaloil-soluble materials and/or water-soluble materials conventionally usedin topical compositions, at their art-established levels.

Various water-soluble materials may also be present in the compositionsof this invention. These include humectants, proteins and polypeptides,preservatives and an alkaline agent. In addition, the topicalcompositions herein can contain conventional cosmetic adjuvants, such asdyes, opacifiers (e.g., titanium dioxide), pigments and perfumes.

The topical compositions of the present invention may also include asafe and effective amount of a penetration enhancing agent. A suitableamount of penetration enhancing agent is from about 1% to about 5% ofthe composition. Examples of useful penetration enhancers, among others,are disclosed in U.S. Pat. Nos. 4,537,776, 4,552,872, 4,557,934,4,130,667, 3,989,816, 4,017,641, and 4,954,487.

Other conventional topical product additives may also be included in thecompositions of the present invention. For example, collagen, hyaluronicacid, elastin, hydrolysates, primrose oil, jojoba oil, epidermal growthfactor, soybean saponins, mucopolysaccharides, and mixtures thereof maybe used.

Various vitamins may also be included in the compositions of the presentinvention. For example, vitamin A, and derivatives thereof, vitamin B2,biotin, pantothenic, vitamin D, vitamin E, and mixtures thereof may beused.

The topical compositions of the present invention may also comprise, inaddition to the active compounds, a cosmetically-acceptable surfactant.The term “cosmetically-acceptable surfactant” refers to a surfactant oremulsifier which is not only an effective skin cleanser, but also can beused without undue toxicity, irritation, allergic response, and thelike. Furthermore, the surfactant or emulsifier should be capable ofbeing commingled with the active compounds in a manner such that thereis no interaction which would substantially reduce the efficacy of thecomposition for regulating skin wrinkles and/or skin atrophy.

The topical compositions of the present invention may contain from about0.1% to about 20%, or from about 1% to about 5%, of the active compoundsand from about 1% to about 90%, or from about 5% to about 10%, of acosmetically-acceptable surfactant.

The surfactant component of the compositions of the present inventionare selected from anionic, nonionic, zwitterionic, amphoteric andampholytic surfactants, as well as mixtures of these surfactants. Suchsurfactants are well-known to those skilled in the detergency art.

Typical examples of suitable mild, i.e. particularly cosmetic,dermatologically or pharmaceutically acceptable emulisifiers orsurfactants are fatty alcohol polyglycol ether sulfates, monoglyceridesulfates, mono- and/or dialkyl sulfosuccinates, fatty acid isethionates,fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates,alpha-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides,fatty acid glucamides, alkylamidobetaines and/or protein fatty acidcondensates. In some embodiments, these are based on wheat proteins.

When formulated as “cleaning compositions”, the topical composition ofthe present invention can optionally contain, at their art-establishedlevels, any additional suitable known materials which are conventionallyused in skin cleansing compositions.

While the compositions described hereinabove might be used in anysuitable format, as described hereinabove, the topical compositions ofthe present invention might additionally comprise any of a number ofadditional materials described hereinabove, or otherwise designed toprovide acceptable application properties, or provide additionalcosmetic, pharmaceutical or dermatological effects. These additionalmaterials can be, for example, superfatting agents, pearlizing waxes,consistency factors, thickeners, polymer additives, silicone compoundsor derivatives, fats, oils, waxes, stabilizers, biogenic agents,deodorizers, anti-dandruff agents, film formers, foam stabilizers,electrolytes, swelling agents, UV protection factors, hydrotropes,preservatives, bactericides, perfumes and/or perfume oils, antifoanis,dyes, pigments which have a coloring effect, moisturizers and/orhumectants, insect repellents, self-tanning agents, solubilizers, germinhibitors, anti-inflammatory agents, benofuran derivatives, retinoids,chelating agents, and the like as further auxiliaries and additives.

The compounds of the invention may also be administered by any otherconvenient route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.) and may be administeredtogether with another biologically active agent. Administration can besystemic or local. Various delivery systems are known, e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc., and can be used to administer a compound of the invention. Incertain embodiments, more than one compound of the invention isadministered to a patient. Methods of administration include but are notlimited to intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intranasal,intracerebral, intravaginal, transdermal, rectally, by inhalation, ortopically, including to the ears, nose, eyes, or skin. The desired modeof administration is left to the discretion of the practitioner, andwill depend, in part, upon the site of the medical condition. In mostinstances, administration will result in the release of the compounds ofthe invention into the bloodstream.

In some embodiments, it may be desirable to administer one or morecompounds of the invention locally to the area in need of treatment.This may be achieved, for example, and not by way of limitation, bylocal infusion during surgery, topical application, e.g., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, saidimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers. In one embodiment,administration can be by direct injection at the site (or former site)of an atherosclerotic plaque tissue.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of the invention can be formulated asa suppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the compounds of the invention can be deliveredin a vesicle, in particular a liposome (see Langer, Science, 1990,249:1527-1533; Treat et al., in Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York,pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.).

In yet another embodiment, the compounds of the invention can bedelivered in a controlled release system. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another embodiment, polymeric materials canbe used (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of the target of the compounds of theinvention, e.g., the liver, thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, in Medical Applications of ControlledRelease, supra, vol. 2, pp. 115-138 (1984)). Other controlled-releasesystems discussed in the review by Langer, 1990, Science 249:1527-1533)may be used.

The present compositions can contain a therapeutically effective amountof a compound of the invention, optionally more than one compound of theinvention, which may be in purified form, together with a suitableamount of a pharmaceutically acceptable vehicle so as to provide theform for proper administration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “vehicle” refers to a diluent, adjuvant, excipient, or carrier withwhich a compound of the invention is administered. Such pharmaceuticalvehicles can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalvehicles can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.When administered to a patient, the compounds of the invention andpharmaceutically acceptable vehicles can be sterile. Water is a suitablevehicle when the compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In some embodiments, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in “Remington's PharmaceuticalSciences” by A. R. Gennaro.

In some embodiments, the compounds of the invention are formulated inaccordance with routine procedures as a pharmaceutical compositionadapted for intravenous administration to human beings. Typically,compounds of the invention for intravenous administration are solutionsin sterile isotonic aqueous buffer. Where necessary, the compositionsmay also include a solubilizing agent. Compositions for intravenousadministration may optionally include a local anesthetic such aslidocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the compound ofthe invention is to be administered by infusion, it can be dispensed,for example, with an infusion bottle containing sterile pharmaceuticalgrade water or saline. Where the compound of the invention isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

The compositions of the invention may also be administered orally.Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions maycontain one or more optionally agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions may be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to 200 milligrams ofa compound of the invention per kilogram body weight. In someembodiments of the invention, the oral dose is 0.01 milligram to 70milligrams per kilogram body weight, or 0.1 milligram to 50 milligramsper kilogram body weight, or 0.5 milligram to 20 milligrams per kilogrambody weight, or 1 milligram to 10 milligrams per kilogram body weight.In some embodiments, the oral dose is 5 milligrams of a compound of theinvention per kilogram body weight. The dosage amounts described hereinrefer to total amounts administered; that is, if more than one compoundof the invention is administered, the preferred dosages correspond tothe total amount of the compounds of the invention administered. Oralcompositions can contain 10% to 95% active ingredient by weight.

Suitable dosage ranges for intravenous (i.v.) administration are 0.01milligram to 100 milligrams per kilogram body weight, 0.1 milligram to35 milligrams per kilogram body weight, and 1 milligram to 10 milligramsper kilogram body weight. Suitable dosage ranges for intranasaladministration are generally about 0.01 pg/kg body weight to 1 mg/kgbody weight. Suppositories generally contain 0.01 milligram to 50milligrams of a compound of the invention per kilogram body weight andcomprise active ingredient in the range of 0.5% to 10% by weight.Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of 0.001 milligram to 200 milligrams per kilogram of body weight.Suitable doses of the compounds of the invention for topicaladministration are in the range of 0.001 milligram to 1 milligram,depending on the area to which the compound is administered. Effectivedoses may be extrapolated from dose-response curves derived from invitro or animal model test systems. Such animal models and systems arewell known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In some embodiments, the kit contains more than onecompound of the invention. In another embodiments, the kit comprises acompound of the invention and another lipid-mediating compound,including but not limited to a statin, a thiazolidinedione, or afibrate.

The compounds of the invention can be assayed in vitro and in vivo, forthe desired therapeutic or prophylactic activity, prior to use inhumans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is suitable for lowering fatty acidsynthesis. The compounds of the invention may also be demonstrated to beeffective and safe using animal model systems.

In certain embodiments of the invention, the compounds of the inventioncan be used in combination therapy with at least one other therapeuticagent. The compound of the invention and the therapeutic agent can actadditively or, more preferably, synergistically. In some embodiments, acomposition comprising a compound of the invention is administeredconcurrently with the administration of another therapeutic agent, whichcan be part of the same composition as the compound of the invention ora different composition.

In some embodiments, a composition comprising a compound of theinvention is administered prior or subsequent to administration ofanother therapeutic agent. As many of the disorders for which thecompounds of the invention are useful in treating are chronic disorders,in one embodiment combination therapy involves alternating betweenadministering a composition comprising a compound of the invention and acomposition comprising another therapeutic agent, e.g., to minimize thetoxicity associated with a particular drug. The duration ofadministration of each drug or therapeutic agent can be, e.g., onemonth, three months, six months, or a year. In some embodiments, when acomposition of the invention is administered concurrently with anothertherapeutic agent that potentially produces adverse side effectsincluding but not limited to toxicity, the therapeutic agent canadvantageously be administered at a dose that falls below the thresholdat which the adverse side is elicited.

A safe and effective amount of an anti-inflammatory agent may thereforebe added to the composition of the present invention, at levels of fromabout 0.1% to about 10%, or from about 0.5% to about 5% of thecomposition. The exact amount of anti-inflammatory agent to be used inthe compositions will depend on the particular anti-inflammatory agencyutilized due to the wide variation in potency of such agents.

Steroidal anti-inflammatory agents, including but not limited to,corticosteroids such as hydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasonedipropionate, clobetasol valerate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, fiucloroloneacetonide, fludrocortisone, flumethasone pivalate, fiuosinoloneacetonide, fiuocinonide, flucortine butylester, fiuocortolone,fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and the balance of itsesters, chloroprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,paramethaso[eta]e, preunisolone, preunisone, beclomethasonedipropionate, triamcinolone, and mixtures thereof may be used. Asuitable steroidal anti-inflammatory for use in the present invention ishydrocortisone.

A second class of anti-inflammatory agents which is useful in thecompositions of the present invention includes the non-steroidalanti-inflammatory agents. Specific non-steroidal anti-inflammatoryagents useful in the composition of the present invention include, butare not limited to: the oxicams, salicylates, acetic acid derivatives,fenamates, propionic acid derivatives, and pyrazoles.

Mixtures of these non-steroidal anti-inflammatory agents may also beemployed, as well as the pharmaceutically-acceptable salts and esters ofthese agents. For example, etofenamate, a fliifenamic acid derivative,is particularly useful for topical application. Of the nonsteroidalanti-inflammatory agents, ibuprofen, naproxen, flufenamic acid,mefenamic acid, meclofenamic acid, piroxicam and felbinac are suitable.In some embodiments, ibuprofen, naproxen, and flufenamic acid aresuitable.

Another class of anti-inflammatory agents which are useful in thepresent invention are the anti-inflammatory agents disclosed in U.S.Pat. No. 4,708,966. This patent reports a class of nonsteroidalanti-inflammatory compounds which comprise specifically substitutedphenyl compounds, especially substituted 2,6-di-tert-butyl phenolderivatives. For example, compounds selected from4-(4′-pentyn-3′-one)-2,6-di-t-butylphenol;4-(5′-hexynoyl)-2,6-di-t-butyl[rho]henol;4-((S)-(31)-3′-methyl-5′-hexynoyl)-2,6-di-t-butylphenol;4-((R)-(+)-3′-methyl-5′-hexynoyl)-2,6-di-t-butylphenol; and4-(3′,3′-dimethoxypropionyl)-2,6-di-t-butylphenol are useful in thepresent invention.

Yet another class of anti-inflammatory agents which are useful in thepresent invention are those disclosed in U.S. Pat. No. 4,912,248 Thispatent reports compounds and diastereomeric mixtures of specific2-naphthyl-containing ester compounds, especially naproxen ester andnaproxol ester compounds, having two or more chiral centers. Forexample, compounds selected from (S)-naproxen-(S)-2-butyl ester,(S)-naproxen-(R)-2-butylester, (S)-naproxol-(R)-2-methyl butyrate,(S)-naproxol-(S)-2-methyl butyrate, diasteromeric mixtures of(S)-naproxen-(S)-2-butyl ester and (S)-naproxen-(R)-2-butyl ester, anddiasteromeric mixtures of (S)-naproxol-(R)-2-methyl butyrate and(S)-naproxol-(S)-2-methyl butyrate are useful in the present invention.

Finally, naturally derived, or so-called “natural” anti-inflammatoryagents are useful in the present invention. For example, candelilla wax,alpha bisabolol, aloe vera, Manjistha (extracted from plants in thegenus Rubia, particularly Rubia Cordifolia), and Guggal (extracted fromplants in the genus Commiphora, particularly Commiphora Mukul), may beused.

The present invention is also directed to the use of a compound offormula I or a pharmaceutically acceptable salt thereof, as describedabove, in the preparation of a medicament for treating or preventing aninflammatory disease, as described herein.

In order that the invention disclosed herein may be more efficientlyunderstood, examples are provided below. It should be understood thatthese examples are for illustrative purposes only and are not to beconstrued as limiting the invention in any manner. Throughout theseexamples, molecular cloning reactions, and other standard recombinantDNA techniques, were carried out according to routine methods known tothose skilled in the art, using commercially available reagents, exceptwhere otherwise noted. In addition, each embodiment disclosed herein canbe combined with any other embodiment disclosed herein.

EXAMPLES Example 1 DTH

In this study, tenilsetam was assessed for its ability to affect thedelayed-type hypersensitivity (DTH) reactions. DTH reactions areantigen-specific cell-mediated immune responses that can mediate harmful(e.g., allergic dermatitis and autoimmunity) aspects of immune function.The immune reaction induced by the method described below ischaracterized by swelling at the site of challenge and by aninfiltration of monocytes/macrophages and lymphocytes into the epidermisand dermis. This model for skin DTH reactions has been used widely tomonitor cell-mediated immune responses in vivo. Prednisolone(dexamethasone), a steroid anti-inflammatory, reduces cell-mediatedimmune responses and was employed to pharmacologically validate theassay.

Materials and Methods. ICR:CD1 male mice (Harlan) 12 to 13 weeks of agewere used for this study. Animals were kept on a 12 hr light dark cycleand fed ad libitum. On day 1 of the study, mice were injected IV with1×10⁶ of washed sheep red blood cells in a volume of 200 μL. Mice wereadministered tenilsetam on day 6. Fifteen minutes after the day 6 drugtreatment mice were injected with SRBC's (1×10⁸) in a volume of 25 μLinto the back left footpad.

On day 7, mice were re-administered drug as above. Footpad thickness ofboth the back right and back left foot pads was measured using a digitalmicrometer. Foot pad thickness of the injected paw was normalized to theuninjected footpad for each animal. Visual observation for inflammatoryconditions was utilized as well.

Data are expressed as the average±SEM. Data were averaged and analyzedby ANOVA followed by a post-hoc Tukey's test with a p value of less then0.05 indicating a statistical difference.

For this study, there were 4 groups: vehicle, and tenilsetam at 3 doselevels: 10, 30 and 100 mg/kg. There were 6 animals per group.

Results. Tenilsetam significantly decreased foot swelling as measuredusing a micrometer and by visual examination. This occurred at all threedoses (10, 30, 100 mg/kg) as shown in FIG. 1.

Example 2 Contact Hypersensitivity

Contact Hypersensitivity (Contact Dermatitis). Contact hypersensitivity(CHS)³ is a T cell-mediated cutaneous immune/inflammatory reaction tohaptens. Oxazolone can be used to evoke a contact hypersensitivityreaction and produce an animal model of contact dermatitis. Tenilsetamwas assessed for its ability to affect oxazolone mediated contactdermatitis reaction.

Materials and Methods. ICR:CD1 male mice (Harlan) 12 to 13 weeks of agewere used for this study. Animals were kept on a 12 hr light dark cycleand fed ad libitum.

Oxazolone sensitization. Mice were exposed to 50 μL of 3% oxazolone (in100% ethanol) via topical application to the skin of the abdomen.Additional exposure was via the 4 paws with a small amount of oxazolone.

Oxazolone challenge. On day 5, both ears of mice were exposed to 1%oxazolone (20 μL per ear; 10 μL/side of ear).

Analysis. On day 6, ears were scored for redness on a 0-3 scoring basisand were measured for thickness using a micrometer. These values wererecorded, group values were averaged and statistical differencesdetermined by ANOVA followed by a Mann-Whitney U-test (for visual score)or by Tukey's test (for ear thickness). A p value of less than 0.05 wasused to indicate statistical significance.

For this study, there were 5 groups: vehicle, and tenilsetam at 3 doselevels: 10, 30 and 100 mg/kg. In addition, there was a dexamethasonegroup. Dexamethasone functioned as the positive control for this study.There were 6 animals per group.

Results. Tenilsetam significantly decreased ear swelling after oxazolonechallenge at all three doses measured. This affect was apparent withvisual scoring and with ear thickness measurements, as depicted in FIG.2.

Example 3 Septic Shock and Inflammation

Lipopolysaccharide General Inflammation. Bolus injection of lethal orsublethal doses of lipopolysaccharide (LPS; the major component ofbacterial cell wall) results in the rapid and transient rise in tumornecrosis factor (TNFα) levels in serum in mammals. This animal model wasdeveloped to mirror certain aspects of septic shock in humans. Thismodel is also an effective first-line general inflammation model and maybe used to determine the anti-inflammatory potential of test compounds.

Materials and methods. Male ICR:CD1 mice (Harlan Sprague Dawley,Indianapolis, Ind.) 9 to 10 weeks of age were housed three per cage,kept on a standard 12 hr light cycle and fed western (high-fat) diet for5.5 weeks for these studies. Mice were provided food and water adlibitum.

Lipopolysaccharide (heat killed E. coli 0127:B5; SigmaAldrich) wasprepared in water at a concentration of 0.025 mg/ml. LPS was dosed at avolume of 10 ml/kg (ip) to produce a final dose of 0.25 mg/kg or 7.5mg/mouse. Tenilsetam was dosed 15 minutes prior to LPS administration.Blood was collected by retrorbital eye bleed 90 minutes after LPSadministration. Plasma was prepared from blood and TNFα levelsdetermined by ELISA as described below.

Serum TNFα levels were determined using the OptEIA™ mouse TNFα ELISA kit(BD Biosciences) as per directions of the manufacturer. Data wereaveraged and analyzed by ANOVA followed by a post-hoc Tukey's test witha p value of less then 0.05 indicating a statistical difference.

For this study, there were 4 groups: vehicle, and Tenilsetam at 3 doselevels: 10, 30 and 100 mg/kg. There were 6 animals per group.

Results. LPS administration in vehicle-treated mice increased serum TNFlevels to approximately 1.8 μg/ml. Tenilsetam administration decreasedTNFα levels at doses of 10 and 30 mg/kg as shown in FIG. 3.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference (including, but not limitedto, journal articles, U.S. and non-U.S. patents, patent applicationpublications, international patent application publications, and thelike) cited in the present application is incorporated herein byreference in its entirety.

1-25. (canceled)
 26. A method of treating delayed-type hypersensitivity,contact dermatitis, atopic dermatitis, or septic shock in a humancomprising administering to the human in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I

and pharmaceutically acceptable carrier, wherein: X is 2-thienyl,3-thienyl, 2-furyl, 3-furyl, or phenyl, each unsubstituted,mono-substituted, di-substituted, or tri-substituted with,independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; R¹ and R⁴ are, independently, H or C₁-C₄ alkyl;R^(2a) and R^(2b) are, independently, H, OH, or C₁-C₄ alkyl, or,together, R^(2a) and R^(2b) are C═O; R^(3a) and R^(3b) are,independently, H, OH, or C₁-C₄ alkyl, or, together, R^(3a) and R^(3b)are C═O; and R^(X) is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; or a pharmaceutically acceptable salt thereof,wherein the compound of formula I is administered in the absence ofanother therapeutic agent.
 27. The method of claim 26 wherein X is2-thienyl, 3-thienyl, 2-furyl, or 3-furyl, each unsubstituted,mono-substituted, or di-substituted with, independently, OH, halogen,C₁-C₄ alkyl, or C₁-C₄ alkoxy.
 28. The method of claim 26 wherein X isunsubstituted 2-thienyl or 2-thienyl mono-substituted with OH, halogen,or C₁-C₄ alkyl.
 29. The method of claim 26 wherein X is unsubstituted2-thienyl.
 30. The method of claim 26 wherein R¹ and R⁴ are H or C₁-C₄alkyl.
 31. The method of claim 26 wherein R^(2a) and R^(2b) are,independently, H or C₁-C₄ alkyl, or, together, R^(2a) and R^(2b) areC═O.
 32. The method of claim 26 wherein R^(2a) and R^(2b) are both H.33. The method of claim 26 wherein R^(3a) and R^(3b) are, independently,H or C₁-C₄ alkyl, or, together, R^(3a) and R^(3b) are C═O.
 34. Themethod of claim 26 wherein R^(3a) and R^(3b) are both H.
 35. The methodof claim 26 wherein R^(X) is H, C₁-C₄ alkyl, or C₁-C₄ alkoxy.
 36. Themethod of claim 26 wherein R^(X) is H.
 37. The method of claim 26wherein: X is unsubstituted 2-thienyl or 2-thienyl mono-substituted withOH, halogen, or C₁-C₄ alkyl; R¹ and R⁴ are, independently, H or C₁-C₄alkyl; R^(2a) and R^(2b) are, independently, H or OH; R^(3a) and R^(3b)are, independently, H or OH; and R^(X) is H.
 38. The method of claim 26wherein: X is unsubstituted 2-thienyl or 2-thienyl mono-substituted withOH, halogen, or C₁-C₄ alkyl; and R¹, R⁴, R^(2a), R^(2b), R^(3a), R^(3b),and R^(X) are H.
 39. The method of claim 26 wherein: X is unsubstituted2-thienyl; and R¹, R⁴, R^(2a), R^(2b), R^(3a), R^(3b), and R^(X) are H.40. The method of claim 26 wherein the pharmaceutical composition isadministered to the human topically.
 41. The method of claim 40 whereinthe pharmaceutical composition is applied to the skin as a topicalcream, liquid solution, or dispersion.
 42. The method of claim 40wherein the pharmaceutical composition is formulated as a bar, liquid,paste, mousse, cream, gel, aerosol, lotion, hair shampoo, hair lotion,beach oil, foam bath, shower bath, alcoholic and aqueous/alcoholicsolution, emulsion, wax/fat compound, stick preparation, spray, powder,or ointment.
 43. The method of claim 40 wherein the pharmaceuticalcomposition further comprises an emollient, thickening agent,emulsifier, humectant, protein, preservative, alkaline agent, dye,opacifier, vitamin, pigment, perfume, penetration enhancing agent, orcosmetically-acceptable surfactant.
 44. The method of claim 40 whereinthe pharmaceutical composition further comprises collagen, hyaluronicacid, elastin, hydrolysate, primrose oil, jojoba oil, epidermal growthfactor, soybean saponin, or mucopolysaccharide, or any mixture thereof.45. The method of claim 40 wherein the pharmaceutical compositionfurther comprises a superfatting agent, pearlizing wax, consistencyfactor, thickener, polymer additive, silicone compound, fat, oil, wax,stabilizer, biogenic agent, deodorizer, anti-dandruff agent, filmformer, foam stabilizer, electrolyte, swelling agent, UV protectionfactor, hydrotrope, preservative, bactericide, perfume, dye, pigment,moisturizer and/or humectant, insect repellent, self-tanning agent,solubilizer, germ inhibitor, benofuran derivative, retinoid, orchelating agent.
 46. The method of claim 26 wherein the pharmaceuticalcomposition is administered to the human orally.
 47. The method of claim46 wherein the pharmaceutical composition is formulated as a tablet,lozenge, aqueous or oily suspension, granule, powder, emulsion, capsule,syrup, or elixir.
 48. The method of claim 46 wherein the pharmaceuticalcomposition contains one or more agents chosen from a sweetening agent,a flavoring agent, a coloring agent, and a preserving agent.
 49. Amethod of treating pruritis in a human comprising administering to thehuman in need thereof a therapeutically effective amount of a compoundof formula I

wherein: X is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, or phenyl, eachunsubstituted, mono-substituted, di-substituted, or tri-substitutedwith, independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; R¹ and R⁴ are, independently, H or C₁-C₄ alkyl;R^(2a) and R^(2b) are, independently, H, OH, or C₁-C₄ alkyl, or,together, R^(2a) and R^(2b) are C═O; R^(3a) and R^(3b) are,independently, H, OH, or C₁-C₄ alkyl, or, together, R^(3a) and R^(3b)are C═O; and R^(X) is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; or a pharmaceutically acceptable salt thereof,wherein the compound of formula I is administered in the absence ofanother therapeutic agent.
 50. A method of treating delayed-typehypersensitivity, contact dermatitis, atopic dermatitis, or septic shockin a human comprising administering to the human in need thereof apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I

and pharmaceutically acceptable carrier, wherein: X is 2-thienyl,3-thienyl, 2-furyl, 3-furyl, or phenyl, each unsubstituted,mono-substituted, di-substituted, or tri-substituted with,independently, OH, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; R¹ and R⁴ are, independently, H or C₁-C₄ alkyl;R^(2a) and R^(2b) are, independently, H, OH, or C₁-C₄ alkyl, or,together, R^(2a) and R^(2b) are C═O; R^(3a) and R^(3b) are,independently, H, OH, or C₁-C₄ alkyl, or, together, R^(3a) and R^(3b)are C═O; and R^(X) is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or (C₁-C₄)alkoxy-(C₁-C₄) alkyl; or a pharmaceutically acceptable salt thereof;wherein the pharmaceutical composition comprises a solvent; and whereinthe pharmaceutical composition is free of a free radical scavenger.